Field of the Invention
The present invention relates to an improved process for preparing simvastatin and more particularly, the improved process for preparing simvastatin expressed by formula 1 with high yield and high purity by performing the following sequential processes comprising:
(i) hydrolysis of lovastatin as starting material with potassium t-butoxide in an organic solvent and small amount of water under a mild reaction condition, followed by lactonization of the obtained solid intermediate with preventing from formation of by-products;
(ii) protection of an alcohol group with t-butyldimethylsilyl group which can be easily removed with concentrated hydrochloric acid without the formation of by-products;
(iii) acylation of the obtained protected intermediate with acyloxytriphenyl phosphonium salt as an acylating agent under a mild reaction condition; and
(iv) removal of the silyl protective group with a concentrated hydrochloric acid.
The present invention is to provide the improved process of preparing simvastatin expressed by formula 1 environmentally sound, economically efficient, and industrially useful. 
Simvastatin of formula 1 is known as antihypercholesterolemic agent that has excellent inhibitory activity of the HMG-Co A reductase and its preparing methods have been also intensively studied. General processes of preparing simvastatin of formula 1 include hydrolysis of lovastatin, lactonization, protection of an alcohol in lactone ring, acylation, and deprotection. Many patents are published with improved process for preparing simvastatin by characterizing each step of the process. Especially, purity of the product varies with the final deprotection step of the process.
When t-butyldimethylsily group is introduced as a protecting group to obtain the compound of formula 2, the deprotection reaction suffers from poor conversion to simvastatin due to formation of by-products such as compounds of formula 3 and formula 4. 
These by-products of the compounds 3 and 4 cannot be easily removed by conventional purifications and thus it affects yield and purity of the final product, simvastatin. Use of t-butylammonium fluoride (TBAF) or hydrogen fluoride (HF) having fluoro anion (Fxe2x88x92) in the deprotection of t-butyldimethylsily group in lactone ring have been reported [J. Org. Chem. 1991, 56, 4929-4932]. However, as shown in scheme 1, the by-product of formula 3 can be generated during prolonged reaction due to a reaction between a fluoro ion (Fxe2x88x92) and an acidic xcex1-proton of the compound of formula 2. Yield of said deprotection with TBAF is 72% [J. Org. Chem. 1991, 56, 4929-4932]. 
U.S. Pat. No. 4,845,237 and Korean Patent No. 133,599 disclose that 0.4-0.8% of the compounds 3 and 4 as by-products are produced during the reaction, resulting decrease in purity.
Another process for preparing simvastatin of formula 1 introduces ring-opening of lactone ring to amide group in order to solve the problem for the formation of by-products as shown in scheme 2 [J. Org. Chem. 1991, 56, 4929-4932]. 
However, this process also have drawbacks: (i) in order to introduce a methyl group on xcex1-position of substituted butylester group in the compound of formula 5, an unstable strong base such as a compound of formula 6, which is not appropriate in industrial scale, has to be used; (ii) a by-product such as a dehydrated unsaturated acid of the compound 9 which is precursor of the compound of formula 3 is produced during the hydrolysis of the compound of formula 7 and the following acidification with hydrochloric acid; (iii) since a high temperature is required to obtain the desired compound of formula 1 from the compound of formula 8, a dimer of the compound of formula 4 is produced as a by-product. 
As described above, many processes still produce by-products such as the compound of formula 3 and the dimer compound of formula 4 and further, these by-products are not easily removed with conventional purifications, resulting low purity of simvastatin of formula 1.
In comparison of conventional removals of a protecting group, the process of scheme 1 is preferable in industrial scale to prepare simvastatin, but it requires improved method promising high yield and high purity without the formation of the by-products of the compounds 3 and 4.
And also, there are series of patents to prepare simvastatin of formula 1 from lovastatin as the starting material, it still requires improvement in hydrolysis and acylation.
As a result of that the inventors have long been engaged in the manufacture of simvastatin and have conducted intensive studies to resolve the drawbacks, the inventors have noted that introduction of t-butyldimethylsilyl(TBDMS) group as an alcohol protection group and construction of deprotection reaction condition not to produce by-products of the compounds 3 and 4 promise highly pure production of simvastatin of formula 1 in high yield.
The present invention is also characterized by the process for preparing from lovastatin to simvastatin, wherein the process is performed under mild condition and by using reagents which are easy handle and industrially useful.
Therefore, an object of the present invention is to provide an economical and efficient process for preparing simvastatin of formula 1 which is useful as the antihypercholesterolemic agent in industrial scale.